Peroxisome proliferator‐activated receptor activity correlates with poor survival in patients resected for hepatocellular carcinoma

Pommergaard, Hans‐Christian; Hasselby, Jane Preuss; Willemoe, Gro Linno; Ralbovska, Adela; Rostved, Andreas Arendtsen; Rasmussen, Allan; Schultz, Nicolai Aagaard; Hillingsø, Jens; Larsen, Peter Nørgaard; Kugler, Jan-Michael

doi:10.1002/jhbp.745

Cited by 7 publications

(4 citation statements)

References 30 publications

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“…In spite of the active ingredients in acRoots for potential anticancer activity, this study further identified 11 key target genes, namely, AKT1, Casp3, EGFR, JUN, ESR1, Cat, PPARG, AR, HIF1A, RELA, and BCL2L1, by combining network pharmacology with WGCNA analysis. Notably, our results are consistent with findings reported in previous studies [35][36][37][38][39][40][41][42][43][44]. Furthermore, GO and KEGG pathway analyses were performed to further illustrate the potential anticancer biological functions and regulatory pathway of acRoots.…”

Section: Discussionsupporting

confidence: 90%

Systems Network Pharmacology-Based Prediction and Analysis of Potential Targets and Pharmacological Mechanism of Actinidia chinensis Planch. Root Extract for Application in Hepatocellular Carcinoma

Yang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Purpose. Traditional Chinese medicine (TCM) sometimes plays a crucial role in advanced cancer treatment. Despite the significant therapeutic efficacy in hepatocellular carcinoma (HCC) that Actinidia chinensis Planch root extract (acRoots) has proven, its complex composition and underlying mechanism have not been fully elucidated. Therefore, this study analyzed the multiple chemical compounds in acRoots and their targets via network pharmacology and bioinformatics analysis, with the overarching goal of revealing the potential mechanisms of the anti-HCC effect. Methods. The main ingredients contained in acRoots were initially screened from the traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the candidate bioactive ingredient targets were identified using DrugBank and the UniProt public databases. Second, the biological processes of the targets of active molecules filtered from the ingredients of acRoots were evaluated using gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Third, weighted gene coexpression network analysis (WGCNA) was performed to identify gene coexpression modules associated with HCC. The hub genes of acRoots in HCC were defined via contrasting the above module eigengenes with candidate target genes of acRoots. Furthermore, the target-pathway network was analyzed to explore the mechanism for anti-HCC effect of hub genes. Kaplan–Meier plotter database analysis was performed to validate the hub genes of acRoots correlation with prognostic values in HCC. In order to verify the results of the network pharmacological analysis, we performed a molecular docking approach on the active ingredients and key targets using the Discovery Studio software. The viability of SMMC-7721 and HL-7702 cells was determined by Cell counting kit-8 (CCK-8) after being treated with different concentrations of (+)-catechin (0, 50, 100, 150, 200, and 250 g/ml) for 24, 48, and 72 hours, respectively. Finally, qRT-PCR and Western blot involving human hepatocarcinoma cells were utilized to verify the impact of (+)-catechin on the hub genes associated with prognosis. Results. 6 out of 26 active ingredients extracted from TCMSP were deemed as the core ingredients of acRoots. 175 bioactive-ingredient targets of acRoots were obtained and a bioactive-ingredient targets network was established correspondingly. The biological processes (BP) of target genes mainly involved processes, such as toxic substance and wounding. The results of KEGG pathways indicated that the target genes were mainly enriched in pathways in cancer, AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, and other pathways. Also, the two hub genes (i.e., ESR1 and CAT) were closely associated with the prognosis of HCC patients. As a consequence, we predicated a series of signaling pathways, including estrogen signaling pathway and longevity regulation pathway, through which acRoots could facilitate the treatment for HCC. The molecular docking experiment ascertained that ESR1 and CAT had an effective binding force with (+)-catechin, one of the core ingredients of acRoots. Furthermore, (+)-catechin inhibited SMMC-7721 cell growth in a dose-dependent manner and a time-dependent manner. Finally, we suggest that the expression level of ESR1 and CAT is positively related to the (+)-catechin concentrations in in-vitro experiments. Conclusion. The bioactive ingredients of acRoots, including quercetin, (+)-catechin, beta-sitosterol, and aloe-emodin, have synergistic interactions in reinforcing the anticancer effect in HCC. Evidently, acRoots took effect by regulating multitargets and multipathways through its active ingredients. Further, (+)-catechin, the possible paramount anti-HCC active ingredient in acRoots, helped improve the prognosis of HCC patients by increasing the expression of ESR1 and CAT. Additionally, the findings yielded provide a conceptual guidance for the clinical treatment of HCC and the methods adopted are potentially applicable in the future comprehensive analysis of the underlying mechanisms of TCMs.

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Section: Discussionsupporting

confidence: 90%

Systems Network Pharmacology-Based Prediction and Analysis of Potential Targets and Pharmacological Mechanism of Actinidia chinensis Planch. Root Extract for Application in Hepatocellular Carcinoma

Yang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…Moreover, Busso-Lopes et al [ 35 ] found that low expression of ALDH7A1 in extracellular vesicles from metastatic lymph nodes is correlated with reduced survival in oral cancer patients. Other prognosis-related mechanisms, such as the activity of peroxisome proliferator-activated receptors and DNA methylation, have also been shown to be influenced by ALDH7A1 expression [ 36 – 38 ]. Thus, the influence of ALDH7A1 on prognosis should be evaluated for individual cancer types.…”

Section: Discussionmentioning

confidence: 99%

The impact of ALDH7A1 variants in oral cancer development and prognosis

Chuang

Chen

et al. 2022

Aging

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The gene encoding aldehyde dehydrogenase 7 family member A1 (ALDH7A1) has been associated with the development and prognosis in multiple cancers; however, the role of ALDH7A1 polymorphisms in oral cancer remains unknown. For this purpose, the influences of ALDH7A1 rs13182402 and rs12659017 on oral cancer development and prognosis were analyzed. Our resulted showed that ALDH7A1 rs13182402 genotype had less pathologic nodal metastasis among betel quid chewer. ALDH7A1 rs13182402 also corresponded to higher expressions in upper aerodigestive mucosa, whole blood, the musculoskeletal system and oral cancer tissues than did the ALDH7A1 wild type. Furthermore, ALDH7A1 overexpression in oral cancer cells increased in vitro migration, whereas its silencing reduced cell migration. Conversely, ALDH7A1 expression in tumor tissues and in patients with advanced disease was lower than that in normal tissues and in patients with early-stage disease. When the patients were classified into ALDH7A1-high and -low-expression groups, the high-ALDH7A1 group had superior outcomes in progression-free survival than the low-ALDH7A1 group (5-year survival of 58.7% vs. 48.0%, P = 0.048) did. In conclusion, patients with high ALDH7A1 expression might, however, have more favorable prognoses than those with low ALDH7A1 expression have.

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“…RNA sequencing was used to evaluate the expression of PPAR in 52 patients undergoing hepatectomy for HCC. The results showed that altered PPAR activity was associated with reduced OS 84 …”

Section: Ppars and Related Pathways As Prognostic Biomarkersmentioning

confidence: 96%

Roles of peroxisome proliferator‐activated receptors in hepatocellular carcinoma

Zhao,

Tan,

Zhang

et al. 2023

J Cellular Molecular Medi

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Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is linked to risk factors such as viral hepatitis, alcohol intake and non‐alcoholic fatty liver disease (NAFLD). Recent advances have greatly improved our understanding that NAFLD is playing a major risk factor for HCC. Peroxisome proliferator‐activated receptors (PPARs) are a class of transcription factors divided into three subtypes: PPARα (PPARA), PPARδ/β (PPARD) and PPARγ (PPARG). As important nuclear receptors, PPARs are involved in many physiological processes, and PPARs can improve NAFLD by regulating lipid metabolism, accelerating fatty acid oxidation and inhibiting inflammation. In recent years, some studies have shown that PPARs can participate in the occurrence and development of HCC by regulating metabolic pathways. In addition, PPAR modulators have been reported to inhibit the proliferation and metastasis of HCC cells and can enhance the curative effect of conventional treatments. This article reviews the role of PPARs in the occurrence and development of HCC, as well as its value in the diagnosis, treatment and prognosis of HCC, in order to provide directions for future research.

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Peroxisome proliferator‐activated receptor activity correlates with poor survival in patients resected for hepatocellular carcinoma

Cited by 7 publications

References 30 publications

Systems Network Pharmacology-Based Prediction and Analysis of Potential Targets and Pharmacological Mechanism of Actinidia chinensis Planch. Root Extract for Application in Hepatocellular Carcinoma

Systems Network Pharmacology-Based Prediction and Analysis of Potential Targets and Pharmacological Mechanism of Actinidia chinensis Planch. Root Extract for Application in Hepatocellular Carcinoma

The impact of ALDH7A1 variants in oral cancer development and prognosis

Roles of peroxisome proliferator‐activated receptors in hepatocellular carcinoma

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